The "metastatic cascade" is a complex process involving an interplay between host defenses and tumor cell subversion of same. The critical events in hematogenous metastasis are tumor cell arrest and/or attachment to endothelium or deendothialinized surfaces, extravasation from the vascular system and tumor cell growth at a secondary site. The interaction between host platelets and circulating tumor cells facilitates tumor cell metastasis by a yet undefined mechanism. We previously proposed that prostacyclin (PGI2) a natural product of the vessel wall and the most potent antithrombotic agent known may function as an endogenous antimetastatic agent. We present evidence that PGI2 prevents tumor cell-platelet interaction in a variety of tumor types; inhibits platelet facilitated tumor cell attachment to plastic plates, type IV collagen and endothelial cells; causes profound changes in tumor cell membrane topology; and significantly inhibits metastasis in vivo. Evidence is presented identifying a tumor cell platelet aggregating factor. We will lay the foundation for a new class of pharmacologic antimetastatic agents which by a unique mechanism stimulate host PGI2 production. Evidence with a pilot compound (nafazatrom) demonstrates significant antimetastic activity in artificial and spontaneous metastasis models. Structurally and mechanistically similar compounds (isoxican, piroxicam, BW755C and phenidone) will be tested. A mechanistically unrelated compound (CP1415) which also stimulates PGI2 production willbe tested. Compounds will be tested in vivo and in vitro for increased PGI2 production (by RIA and HPLC) by mouse aorta, endothelial cells and aortic smooth muscle cells. Inhibition of metastasis (artificial and spontaneous) will be tested in vivo along with increased survival following removal of the primary. The research should yield important data relevant to a new class of antitumor/antimetastic agents with direct applicability to human cancer.